This is a competing renewal application of an NCDDG program whose initial goals were to understand the basic mechanisms of cytopathology of HIV and feline immunosuppressive retroviruses. These studies were based on the rationale that if we understand the mechanisms of HIV cytopathology, they could be targeted for rational drug design. Thus, our strategy was to target the mechanisms of pathogenesis (assuming the ability to injure T4 cells is the principal mechanism of HIV pathogenesis) rather than the mechanisms of HIV infection/replication. The overall goals of this new application, however, encompass both: 1) continuing and finishing the studies initiated two years ago on the mechanisms of cytopathology and 2) pursuing the understanding of some new phenoma involving basic processes of HIV infection/replication. The studies of the molecular mechanisms of cytopathology include: 1) identification and characterization of the membrane "lesions" induced by HIV, 2) how HIV alters membrane lipid biosynthesis at the cellular and organism levels, and 3) in parallel studies, how feline lentivirus (FIV) induces cytopathology and how FeLV (FAIDS model) induces "programmed cell death" (apoptosis) as its mechanism of cell injury. Feline retrovirus immunodeficiencies are studied as models of pathogenesis. The studies of HIV infection/replication will concentrate on two aspects: 1) the role of elevated intracellular free calcium in HIV replication, focusing particularly on the early events of replication, and 2) determining how normal T4 lymphocytes from certain individuals are resistant to infection by certain HIV-1 isolates. These projects arose from findings of the initial NCDDG studies in which we found that HIV induces a rise in intracellular calcium which appears to be important in "conditioning" the cell for efficient replication and that a polymorphic gene(s) in humans confers resistance to infection to certain HIV-1 isolates at the T4 cell level. We hypothesize that understanding the mechanism of this resistance may lead to new approaches for eventual HIV drug therapy.